What is Multiple Sclerosis?

Multiple Sclerosis (MS) is a chronic immune-mediated disease characterized by multifocal inflammatory demyelination, axonal degeneration, and glial scar formation in the Central Nervous System (CNS). Clinical manifestations include cognitive decline, fatigue, muscle weakness, sensory abnormalities, ataxia, and progressive neurological disability. With approximately 2.8 million patients globally, MS predominantly affects young adults aged 20-40 and is the leading cause of non-traumatic neurological disability in this age group.Based on its natural history, MS is classified into four phenotypes: Relapsing-Remitting MS (RRMS, 80%), Secondary Progressive MS (SPMS), Primary Progressive MS (PPMS, 10%~15%), and Progressive Relapsing MS (PRMS, <5%).
 

Pathogenesis
 

The pathogenesis of MS follows the classic pattern of peripheral initiation and central perpetuation. It begins in genetically susceptible individuals when immune tolerance is broken by environmental triggers (e.g., EBV infection). This leads to the abnormal activation of peripheral myelin-reactive CD4⁺ T cells (primarily Th1 and Th17 subsets).
 

These cells subsequently upregulate chemokine receptors (e.g., CCR6, CXCR3) and interact via surface adhesion molecules (e.g., LFA-1) with ligands (e.g., ICAM-1, VCAM-1) on Blood-Brain Barrier (BBB) endothelial cells. Concurrently, they release matrix metalloproteinases (e.g., MMP-9) that degrade the extracellular matrix, facilitating BBB breakdown and invasion into the CNS. Inside the CNS, activated T cells encounter local antigen-presenting cells (e.g., activated microglia and infiltrating macrophages), undergoing secondary sensitization that dramatically amplifies the inflammatory cascade.

CD4⁺ T cells release large quantities of pro-inflammatory cytokines such as Tumor Necrosis Factor-alpha (TNF-α) and Interferon-gamma (IFN-γ). TNF-α, by activating downstream signaling pathways like NF-κB via its receptor, not only directly induces oligodendrocyte apoptosis and myelin damage but also further disrupts BBB integrity, creating a vicious cycle. Simultaneously, activated CD8⁺ cytotoxic T cells directly kill oligodendrocytes expressing myelin antigens by releasing perforin (Prf1) and granzymes.

(Image placeholder: Brain organoid methodologies to explore mechanisms of disease in progressive multiple sclerosis)
 

In the chronic inflammatory environment, microglia are persistently and abnormally activated via signaling pathways such as TREM2-DAP12 and CX3CR1, polarizing into pro-inflammatory M1 or Disease-Associated Microglia (DAM) phenotypes. Their metabolic pathways, including PI3K-Akt/mTOR, become dysregulated. This leads microglia to continuously release neurotoxic substances like TNF-α, IL-1β, and Reactive Oxygen Species (ROS), and produce cytokines such as GM-CSF that further recruit peripheral immune cells. Together, they create and maintain a potent inhibitory inflammatory microenvironment. This severely hampers the remyelination repair process mediated by the differentiation of oligodendrocyte precursor cells into mature cells and directly causes mitochondrial dysfunction and chronic axonal degeneration and injury. Ultimately, irreversible axonal loss and neuronal death form the basis for permanent neurological deficits and drive disease transition from Relapsing-Remitting MS (RRMS) to Secondary Progressive MS (SPMS) or Primary Progressive MS (PPMS).

(Image placeholder: Microglia in the context of multiple sclerosis)

Mouse Models
 

Prf1-KO Mice: Knockout of the perforin gene Prf1. These mice exhibit significantly alleviated clinical symptoms, with markedly reduced CNS inflammatory infiltration, demyelination, and axonal damage.
 

● TNF-α-KO Mice: Knockout of Tumor Necrosis Factor-alpha (TNF-α). These mice show attenuated CNS inflammatory responses, reduced BBB disruption, and decreased demyelination and oligodendrocyte loss.
 

● IL-23p19-KO Mice: Knockout of the specific p19 subunit of IL-23. Pathogenic Th17 cell responses are significantly weakened in these mice, leading to reduced incidence, delayed onset, and lessened severity in Experimental Autoimmune Encephalomyelitis (EAE), along with decreased recruitment of inflammatory cells into the CNS.
 

● CX3CR1-GFP Mice: By knocking in the Green Fluorescent Protein (GFP) gene at the Cx3cr1locus, which is specifically expressed in microglia, these mice allow for direct visualization of microglial morphology dynamics, distribution, migration, and interactions with surrounding neurons and synapses during health, inflammation (e.g., EAE), and neurodegeneration.
 

MingCeler Biotech Facilitates Gene Therapy Research
 

Gene therapy offers hope for rare diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has established multiple rare disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target genomic locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as two months.

MingCeler Biotech can customize various MS mouse models according to client needs, such as Prf1-KO, TNF-α-KO, IL-23p19-KO, and CX3CR1-GFP mice. We welcome inquiries.

 

References：

[1] Wang Qian, Lu Zhengqi, Li Rui. Treatment Progress of Multiple Sclerosis [J]. Journal of Chongqing Medical University, 2024, 49(5): 597-600. DOI: 10.13406/j.cnki.cyxb.003500

[2] Patil, M.S.; Lin, L.Y.; Marsh-Wakefield, F.; James, E.J.; Palendira, M.; Hawke, S.; Grau, G.E. Multiple Sclerosis: Immune Cells, Histopathology, and Therapeutics. Sclerosis 2024, 2, 117-139.

[3] Zhang X, Chen F, Sun M, Wu N, Liu B, Yi X, Ge R, Fan X. Microglia in the context of multiple sclerosis. Frontiers in Neurology. 2023 Jun 9; 14: 1157287. doi: 10.3389/fneur.2023.1157287.[4] Simões-Abade MBC, Patterer M, Nicaise AM, Pluchino S. Brain organoid methodologies to explore mechanisms of disease in progressive multiple sclerosis. Frontiers in Neurology. 2023; 14: 1157287. doi: 10.3389/fneur.2023.1157287.

 

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